Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration

Abstract

BackgroundType 2 diabetes mellitus (T2DM) and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM.HypothesisLimited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration.MethodsLong Evans rat pups were treated with N-nitrosodiethylamine (NDEA) by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD) or low fat (5%; LFD) chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF) deficiency and resistance in the context of neurodegeneration.ResultsHFD ± NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT), which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD ± NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3β (reflecting increased GSK-3β activity), glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats.ConclusionsEarly limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of ceramides and probably other toxic lipids in brain.

Insulin Resistance, Cognitive Impairment and Neurodegeneration: Roles of Nitrosamine Exposure, Diet and Lifestyles

“…These disease states are linked by the presence of hepatic steatosis or steatohepatitis with hepatic insulin resistance, endoplasmic reticulum (ER) stress, and increased generation of cytotoxic sphingolipids, including ceramides (de la Monte, Tong et al 2006;Lester-Coll, Rivera et al 2006;Moroz, Tong et al 2008;Lyn-Cook, Lawton et al 2009;Tong, Neusner et al 2009;Tong, Longato et al 2010). Mechanistically, inflammation, superimposed on disease states that promote lipid storage in hepatocytes, results in progressive ER stress, oxidative damage, mitochondrial dysfunction, and lipid peroxidation, which together promote hepatic insulin resistance (Capeau 2008;Kraegen and Cooney 2008).…”

Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease

“…Correspondingly, neurocognitive deficits and brain insulin resistance occurred primarily when chronic high calorie feeding resulted in visceral obesity with steatohepatitis. Moreover, a number of examples showed that high fat intake and obesity were not required, and instead, toxin exposures that caused steatohepatitis with hepatic insulin resistance also resulted in neurodegeneration and cognitive impairment (19,33, 49, 50,66,67). These observations suggest that hepatic insulin resistance may mediate neurodegeneration.…”

“…Nnitrosodiethylamine (NDEA), and determined the long-term effects on insulin/IGF signaling networks in the body, liver, and brain. Those studies revealed that low-dose NDEA exposures cause T2DM, non-alcoholic steatohepatitis, visceral obesity, cognitive impairment, and AD-type neurodegeneration with peripheral, hepatic, and brain insulin resistance (66,67), similar to the effects of streptozotocin. Moreover, the adverse effects of NDEA on neuro-cognitive deficits, peripheral, hepatic, and brain insulin resistance, steatohepatitis, and neurodegeneration were exacerbated by chronic high fat diet feeding (142,143).…”

“…Ceramides are lipid signaling molecules (73) that cause insulin resistance (74)(75)(76) by activating pro-inflammatory cytokines (73,77,78) and impairing PI3 kinase-Akt activation (79)(80)(81)(82). Hepatic ceramide production increases in various models of steatohepatitis, including diet-induced obesity (DIO) and low-level nitrosamine exposure (19,33,49,66,67), and each is associated with cognitive impairment, brain insulin resistance, and neurodegeneration. This point led us to formulate the hypothesis that, in the settings of obesity, T2DM, and other peripheral insulin resistance states, cognitive impairment is mediated via a liver-brain axis of neurodegeneration (83)(84)(85).…”

“…Author Manuscript (19,33, 49,66,67), and each is associated with cognitive impairment, brain insulin resistance, and neurodegeneration. This point led us to formulate the hypothesis that, in the settings of obesity, T2DM, and other peripheral insulin resistance states, cognitive impairment is mediated via a liver-brain axis of neurodegeneration (83-85).…”